PROJECT 1: SUMMARY/ABSTRACT Michelle M. Mielke, Ph.D. Hysterectomy is the second most common major surgical procedure performed among women living in the United States after cesarean section. Among women who undergo hysterectomy, 23% aged 40-44 years and 45% aged 45-49 years undergo bilateral salpingo-oophorectomy (BSO) at the same time to prevent ovarian cancer. Although premenopausal BSO is associated with a significant reduced risk of ovarian and breast cancer, there is increasing concern that BSO may have harmful long-term effects which can negate some of the benefits conferred by protection from cancer. Ovaries are both endocrine and reproductive organs. They secrete hormones before menopause (primarily estrogen, progesterone, and testosterone) and after (primarily testosterone, androstenedione, and dehydroepiandrosterone). Thus, reduced ovarian function, especially as caused by the removal of ovaries, can impact multiple systems throughout the lifespan. Prior to menopause, ovarian removal causes significant endocrine disruption. The practice of prophylactic BSO is now declining. However, given the large number of women who have undergone abrupt endocrine disruption by premenopausal BSO over the past decades, there is an urgent need to understand the impact on long-term physical and cognitive function. In addition, elucidating the underlying biological mechanisms may help to delay or prevent the potential negative consequences of premenopausal BSO as these women age. The overall aim of Project 1 is to better understand the long-term functional and cognitive effects and the potential underlying mechanisms resulting from abrupt premenopausal endocrine dysfunction. Recent studies suggest that premenopausal BSO may be associated with accelerated aging. However, the underlying biological mechanisms have not been examined, other than DNA methylation. In addition, it is not clear whether the endocrine disruption that results from premenopausal BSO has a global effect on all physical and cognitive functions, or whether specific domains of physical or cognitive function are more affected than others. We hypothesize that the abrupt and significant endocrine disruption caused by premenopausal BSO will contribute to accelerated aging, as measured by a greater decline in physical and cognitive function and by higher plasma levels of senescence associated secretory phenotype (SASP) proteins compared to referents. To test these hypotheses, we will utilize an established and well-characterized population-based cohort of women with and without premenopausal BSO, who are now only passively followed through the Rochester Epidemiology Project medical-records linkage system. We will recruit, for an in-person study, 250 women with and 250 women without premenopausal BSO a median of 22 years after their surgery or index date. We will extensively characterize their physical and cognitive function and collect blood samples to measure SASP proteins, a novel marker of aging. Studying women who underwent BSO in the past decades provides a unique natural experiment to understand the effects of endocrine function in regulating the pace of aging.